NON-INVASIVE PRENATAL TESTING FOR ADULT-ONSET CONDITIONS: REPRODUCTIVE CHOICE AND THE WELFARE OF THE FUTURE CHILD.

• Date: 01 April 2022
• Author: Taylor-Sands, Michelle,Bowman-Smart, Hilary
• Published date: 01 April 2022
• Author: Taylor-Sands, Michelle

Contents I Introduction II NIPT and Current Relevant Guidelines A Current NIPT Technology and the Regulatory Landscape B General Guidelines on Prenatal Testing C Specific Guidelines on Prenatal Testing for Huntington's Disease D Guidelines on Predictive Testing of Minors III Relevant Interests and Legal Principles A Introduction B Interests of Prospective Parents 1 Principle of Bodily Integrity 2 Principle of Reproductive Autonomy (a) Duty to Inform Pregnant Women about Screening and Treatment Options (b) Clinical and Personal Utility of NIPT 3 Role of Law in Balancing the Interests of the Pregnant Woman and the Future Child (a) Antenatal Behaviour (b) Prenatal Injury C Welfare and Interests of the Future Child D Interests of Broader Society IV A Facilitative Approach to Regulating NIPT A Should NIPT Be Regulated by the State? B A Comparator: Regulation of PGT C A Relational Approach to Reconciling Interests D Recommendations for Future Reform V Conclusion I Introduction

Prenatal genetic testing is often perceived as a routine aspect of antenatal care. With the introduction of non-invasive prenatal testing ('NIPT'), it is easier and safer to access screening for a wide variety of genetic conditions. NIPT involves testing a sample of a pregnant woman's blood, which contains cell-free fetal DNA ('cffDNA'). NIPT has high accuracy for certain conditions, is less invasive than other prenatal testing, and can be done very early in gestation (10-12 weeks). (1) NIPT is already publicly subsidised in some countries, such as Belgium, (2) and is available on a private basis in others, including Australia. NIPT is currently used to screen for conditions such as trisomy 21 ('Down Syndrome'), which are immediately apparent at birth. NIPT may also be used in the future to detect adult-onset disorders and risk profiles for conditions which manifest later in life, including through whole genome sequencing.

Expanded prenatal testing has the potential to enhance reproductive choice and informed decision-making. However, the use of NIPT to detect adult-onset conditions raises significant ethical concerns about the welfare of the future child, particularly where a woman chooses to continue a pregnancy following a fetal diagnosis. Prenatal testing for disorders that are immediately apparent at birth, or apparent soon after, poses comparatively few ethical concerns compared to testing for those that manifest later in life. In this article, we focus on the impact of predictive testing for adult-onset conditions on the welfare of the future child and whether this should influence the ability of prospective parents to access such prenatal testing. Prospective parents with a known genetic risk for a specific genetic disease generally undertake invasive diagnostic techniques such as chorionic villus sampling to find out if their fetus has this serious condition. In the near future, however, prospective parents with no known history of genetic disease (and who would not ordinarily consider invasive testing) may be persuaded by the low risk and ease of NIPT to test for adult-onset conditions as part of a suite of genetic tests. This is more likely if NIPT replaces the combined first-trimester screening test and is publicly subsidised. (3) NIPT differs from other forms of prenatal testing as it significantly lowers the barrier for accessing fetal information and is more likely to be implemented as a routine part of prenatal care than more invasive diagnostic tests. Trisomy 21 screening programs have a very high uptake, and NIPT is more accurate and soon may be more cost-effective for public healthcare systems than the commonly used current method of combined first-trimester screening.

Although NIPT is not specifically regulated by law, access to this technology is influenced by a combination of professional standards, clinical guidelines and common law principles. Current clinical guidelines highlight a fundamental tension between the interests of prospective parents in making genuinely informed reproductive decisions and the interests of a future child in protection from psychosocial harm, preservation of future autonomy, and nondiscrimination. In this article, we unpack these interests by analysing relevant legal and ethical principles applicable to NIPT, with a view to clarifying the specific nature of the interests at stake, the ways in which they collide and intersect, and how they might be managed. We also briefly explore broader societal interests in limiting the scope of NIPT based on concerns about 'designer babies' and eugenics in determining what role, if any, the state has in regulating access to NIPT. Attempts by courts and policymakers to balance the interests of prospective parents with those of the future child and broader society typically employ the language of 'rights', which does not necessarily capture the complex and interconnected nature of the interrelated interests within families. In this article, we frame our discussion within a relational approach that acknowledges the various individual and interconnected interests at stake throughout pregnancy and beyond. There is currently some recognition of the relational nature of the interests of a child within a family in international guidelines on predictive testing of minors. We build on this approach in proposing a regulatory framework for NIPT.

We begin in Part II by briefly explaining the current status of NIPT technology, before outlining existing guidelines on prenatal and genetic testing, some of which reflect a 'facilitative approach' and others a more 'restrictive approach' to testing. In Part III, we explore the interests of prospective parents and the future child, the interrelationship between them, and how the law has managed the tension between these interests in other contexts. In particular, we examine how the legal principles of bodily integrity and reproductive autonomy have been applied in cases involving refusal of treatment by pregnant women, (4) potentially harmful antenatal behaviour, and prenatal injury. We also critique the ethical and empirical bases for concerns raised about the welfare of the future child in the context of NIPT. Finally, we discuss the broader interests within society in promoting equity and reducing discrimination. In Part IV, we propose a facilitative approach to regulating NIPT for adult-onset conditions that promotes reproductive choice and protects the welfare of the future child. We draw on current regulation of pre-implantation genetic testing ('PGT') in Australia and propose a relational approach to accommodate the various interests at stake in NIPT. We conclude in Part V that this approach could be adapted to apply to NIPT more broadly as this procedure becomes commercially available for a broad range of single-gene disorders, polygenic disease susceptibilities, and other information that can be gained from the whole-genome sequencing of a fetus.

II NIPT and Current Relevant Guidelines

A Current NIPT Technology and the Regulatory Landscape

As previously stated, NIPT is safe, has high accuracy for certain conditions, and can be done early in pregnancy. However, it is important to note that NIPT is a screening rather than diagnostic test (that is, it cannot say definitively whether the fetus has the condition or not). This means that if a high-chance result is received (eg for trisomy 21), it is recommended that it be confirmed through prenatal diagnosis techniques such as amniocentesis before any decision is made regarding pregnancy management (5) as false positives and false negatives are still possible with NIPT. (6) However, recent developments using fetal cells rather than cffDNA may allow for these techniques to become diagnostic in the future. (7)

NIPT can also be used for sex determination, which has raised concerns about sex-selective termination of pregnancy. (8) In the near future, the availability of NIPT is likely to be significantly expanded to include testing for single-gene disorders (9) and high-depth whole-genome sequencing, (10) essentially enabling prospective parents to test for any condition with a genetic basis. Predictive testing can include predictors for adult-onset disease such as the BRCA1 variant for breast or ovarian cancer, (11) or the ApoE4 variant for early-onset Alzheimer's disease. (12) With the advent of whole-genome sequencing, NIPT could also be expanded to encompass genomic predictions for disease susceptibility, known as polygenic risk scores. These may include a variety of diseases with a polygenic basis, such as type 2 diabetes (13) or mental illness. (14) Predictive testing can also encompass serious single-gene disorders such as Huntington's disease, for which NIPT has been demonstrated in a research context, although it is not currently available to consumers. (15)

Different adult-onset conditions vary in a number of important ways. One factor is treatability or actionability. Huntington's disease is not considered clinically actionable as there is little to be done to prevent or modify the course of the disease. (16) By way of contrast, detecting the BRCA1 variant can lead to treatments to prevent the onset of breast cancer, such as a preventive mastectomy. (17) These conditions also differ in penetrance. Having the genetic basis for Huntington's disease means that one will develop the disease (although a lower number of trinucleotide repeats does have incomplete penetrance). (18) However, while having the BRCA1 variant increases breast cancer risk considerably, it does not guarantee that one will develop breast cancer. (19) The use of polygenic risk scores raises its own questions; their validity, level of predictiveness and utility in the clinical setting have been criticised. (20) For example, they demonstrate an association, rather than a causal relationship. (21) Furthermore, pleiotropic effects, where a genetic variant can affect multiple traits, may...